TY - JOUR

T1 - Sp1-independent downregulation of NHEJ in response to BER deficiency

AU - Loshchenova, Polina S.

AU - Sergeeva, Svetlana V.

AU - Limonov, Dmitry V.

AU - Guo, Zhigang

AU - Dianov, Grigory L.

N1 - Copyright © 2019 Elsevier B.V. All rights reserved.

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Base excision repair (BER) is the major repair pathway that removes DNA single strand breaks (SSBs) arising spontaneously due to the inherent instability of DNA. Unrepaired SSBs promote cell-cycle delay, which facilitates DNA repair prior to replication. On the other hand, in response to persistent DNA strand breaks, ATM-dependent degradation of transcription factor Sp1 leads to downregulation of BER genes expression, further accumulation of SSBs and renders cells susceptible to elimination via apoptosis. In contrast, many cancer cells are not able to block replication and to downregulate the expression of Sp1 in response to DNA damage. However, knockdown of BER in cancer cells leads to the accumulation of DNA double strand breaks (DSBs), suggesting deficiency in non-homologous end joining (NHEJ) repair of DSBs. Here we investigated whether DNA repair deficiency caused by knockdown of the XRCC1 gene expression in proliferating cells results in downregulation of NHEJ genes expression. We find that knockdown of the XRCC1 gene expression does not cause degradation of Sp1, but leads to downregulation of Lig4/XRCC4 and Ku70/80 at the transcription and protein levels. We thus propose the existence of Sp1-independent backup mechanism that in response to BER deficiency downregulates NHEJ in proliferating cells.

AB - Base excision repair (BER) is the major repair pathway that removes DNA single strand breaks (SSBs) arising spontaneously due to the inherent instability of DNA. Unrepaired SSBs promote cell-cycle delay, which facilitates DNA repair prior to replication. On the other hand, in response to persistent DNA strand breaks, ATM-dependent degradation of transcription factor Sp1 leads to downregulation of BER genes expression, further accumulation of SSBs and renders cells susceptible to elimination via apoptosis. In contrast, many cancer cells are not able to block replication and to downregulate the expression of Sp1 in response to DNA damage. However, knockdown of BER in cancer cells leads to the accumulation of DNA double strand breaks (DSBs), suggesting deficiency in non-homologous end joining (NHEJ) repair of DSBs. Here we investigated whether DNA repair deficiency caused by knockdown of the XRCC1 gene expression in proliferating cells results in downregulation of NHEJ genes expression. We find that knockdown of the XRCC1 gene expression does not cause degradation of Sp1, but leads to downregulation of Lig4/XRCC4 and Ku70/80 at the transcription and protein levels. We thus propose the existence of Sp1-independent backup mechanism that in response to BER deficiency downregulates NHEJ in proliferating cells.

KW - Base excision repair (BER)

KW - DNA damage

KW - Genome stability

KW - Non-homologous End joining (NHEJ)

KW - Transcription factor Sp1

KW - Cell Line

KW - Cell Proliferation

KW - Signal Transduction

KW - Sp1 Transcription Factor/metabolism

KW - Down-Regulation

KW - Humans

KW - X-ray Repair Cross Complementing Protein 1/genetics

KW - DNA Breaks, Double-Stranded

KW - Gene Knockdown Techniques

KW - DNA End-Joining Repair

KW - DNA Repair

UR - http://www.scopus.com/inward/record.url?scp=85080828262&partnerID=8YFLogxK

U2 - 10.1016/j.dnarep.2019.102740

DO - 10.1016/j.dnarep.2019.102740

M3 - Article

C2 - 31812125

AN - SCOPUS:85080828262

VL - 86

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

M1 - 102740

ER -